When therapeutic drugs are administered, body metabolism performs a series of reactions which change the chemical structure of the administered drug. Typically, the drug will be metabolized by more than one pathway. In this manner, the drug is bioconverted, either partially or completely, into its intermediates or metabolites. This is known as biotransformation. The chemical reactions occurring during biotransformation of a drug are classified as phase-I and phase-II. Phase-I reactions are functionalization reactions and involve the conversion of the drug to its metabolites by oxidation, reduction or hydrolysis. Phase-II reactions are conjugation reactions and involve the coupling between the drug or its metabolite and an endogenous substrate.
Although initially described in the liver (see Goodman and Gilman's The Pharmacological Basis of Therapeutics, pp. 13-21, 7th edition, 1985) and in other internal organs, it is now known that biotransformation enzymes are also present in the cells of the skin. During transdermal delivery of a drug, a portion of drug may become altered by the action of these enzymes. In fact, the very presence of the drug may cause levels of enzymes to increase due to the phenomenon of induction. This contributes to the drug's biotransformation.
The biological function of biotransformation is to facilitate elimination of the drug, since generally the metabolites formed are more water soluble than the drug and thus are more readily excreted. However, it is known that some intermediates in the chemical pathway can be more reactive than the parent compound, and thus may tend to react with tissue constituents and be retained for longer periods of time.
It is known in the art that the activity of drug-metabolizing enzymes can be modified by administration of metabolic modulators. For example, the activity of monoamine oxidases in the brain is associated with depression and the activity of these enzymes can be affected by the administration of anti-depressant metabolic modulators. This type of therapeutic administration of metabolic modulators to humans has been mainly for the purpose of affecting the metabolism of endogenous compounds, i.e. those which occur naturally in the body. The inventors are, however, unaware of any disclosure teaching the administration of metabolic modulators for the specific purpose of reducing sensitization or irritation by inhibiting the metabolism of externally applied drugs in the skin or mucosa.